Abstract 3530: The parathyroid hormone-related peptide region likely features seven discrete breast cancer susceptibility loci

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in the mechanism by which breast cancers establish and grow as metastases in bone. Paradoxically, a prospective clinical study clinical suggests that its production early in breast cancer in a cancer is actually protective. Multiple recent Genome-Wide Association Studies (GWAS) have confirmed a single susceptibility locus immediately upstream of the PTHLH gene to be associated with breast cancer. In this study we compare the findings of two GWAS, the ABCFS and the MCCS, along with a large imputed meta-analysis combining the ABCFS, BBCS, DFBBCS, MARIE, SASBAC, HEBCS, GC-HBOC, UK2, BPC3, BCFR and SardiNIA data. To better discern the signals of association with common variant Single Nucleotide Polymorphisms (SNPs) in the PTHLH gene region, we compare results from a conventional marginal analysis performed by plink with those from DepTH, a novel bootstrap permutation-based method that considers multiple contiguous SNPs. These are plotted on the genome and analysed in conjunction with hapmap, encode expression and regulation, genome-wide epistasis, eQTLs, and genetic data. Whereas the classic approach identifies only one SNP (“top hit”), our analysis suggests there are at least 7 discrete regions in and around PTHLH in which there are susceptibility variants, rare or common, with potentially independent functions on disease risk. In addition, exhaustive genome-wide epistasis demonstrates statistical interactions between PTHLH and multiple other gene regions including calcitonin and the vitamin D receptor in breast cancer. Citation Format: Adam N. Freeman, Terence ‘Jack’ Martin, Michael Henderson, Enes Makalic, Daniel F. Schmidt, Miroslaw K. Kapinski, Melissa C. Southey, Graham G. Giles, John L. Hopper. The parathyroid hormone-related peptide region likely features seven discrete breast cancer susceptibility loci. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3530. doi:10.1158/1538-7445.AM2014-3530